PRS (prolyl-tRNA synthetase) is an enzyme group of aminoacyl-tRNA synthetase (ARS) family and serves to activate an amino acid for protein synthesis. That is, ARS performs a translational function to form an aminoacyl adenylate (AA-AMP) and then transfer the activated amino acid to the 3-end of the corresponding tRNA. Since ARS plays an important role in the synthesis of protein, ARS inhibitors suppress the growth of all cells. Thus, ARS has been recognized as a promising target for a therapeutic agent for treating diseases that should suppress antibiotics or cell overexpression (Nature, 2013, 494:121-125).
PRS is present in, or functions as, a multisynthetase complex (MSC) in the form of EPRS (Glutamyl-Prolyl-tRNA Synthetase). In particular, among various MSCs, EPRS has been reported to be closely associated with various solid tumors (see, Nat. Rev. Cancer, 2011, 11, 708-718). In recent years, it has been reported that EPRS is overexpressed in PANC-1 cells which are pancreatic cancer cells (J. Proteome Res, 2012, 11: 554-563).
It has been known that EPRS is separated from MSC through the stimulation of interferon-gamma to form GAIT (Gamma-Interferon Activated Inhibitor of Translation) complex, thereby suppressing the synthesis of different inflammatory protein including Cp (ceruloplasmin) (Cell, 2012, 149: 88-100).
The only substance, known as the PRS inhibitor, is halofuginone. Halofuginone is a derivative of febrifugine derived from natural products and have anti-malarial effects and various anti-inflammatory effects. It can also be used as an animal feed additive. Currently, halofuginone is being clinically studied as anti-cancer agent, an anti-inflammatory agent (J Immunol, 2014, 192(5), 2167-76), therapeutic agents for the treatment of autoimmune diseases (Arthritis Rheumatol, 2014, 66 (5), 1195-207), and therapeutic agents for the treatment of fibrotic diseases (World J Gastroenterol, 2014, 20 (40), 14778-14786) (Bioorg. Med. Chem. 2014, 22, 1993-2004).
However, it has been reported that halofuginone acts on various targets and has a very severe toxicity (Bioorg. Med. Chem. Lett., 2007, 17: 4140-4143), and further there is a risk of genotoxicity (The EFSA Journal, 2003, 8: 1-45). Therefore, discovering PRS inhibitors having higher safety to the human body among substances capable of inhibiting PRS like halofuginone has a significance in terms of developing an anti-cancer agent of the next generation that can be used as an antifibrosis agent, an anti-inflammatory agent, an autoimmune therapeutic agent alone or in combination with an existing targeted anti-cancer agent.
In this regard, the present inventors have conducted numerous studies to develop a novel small molecule compound with reduced toxicity while having a PRS enzyme inhibitory effect, and found that the compound having a novel structure which will be described later selectively inhibits the PRS, thereby completing the present invention.